S182: ORAL IPTACOPAN MONOTHERAPY INCREASES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) RED BLOOD CELL CLONE SIZE VIA CONTROL OF INTRA- AND EXTRAVASCULAR HEMOLYSIS IN ANTI-C5-TREATED PNH PATIENTS WITH ANEMIA
Authors: Antonio Maria Risitano, Alexander Röth, Austin Kulasekararaj, Phillip Scheinberg, Yasutaka Ueda, Carlos de Castro, Eros DI Bona, Morag Griffin, Saskia Langemeijer, Hubert Schrezenmeier, Wilma Barcellini, Vitor Aq Mauad, Jens Panse, Philippe Schafhausen, Suzanne Tavitian, Eloise Beggiato, Anna Gaya, Wei-Han Huang, Toshio Kitawaki, Abdullah Kutlar, Jaroslaw P Maciejewski, Rosario Notaro, Vinod Pullarkat, Jörg Schubert, Louis Terriou, Michihiro Uchiyama, Flore Sicre de Fontbrune, Luana Marano, Ferras Alashkar, Shreyans Gandhi, Cécile Kerloëguen, Rakesh Kumar, Christine Thorburn, Samopriyo Maitra, Marion Dahlke, Régis Peffault de Latour
Journal: HemaSphere (2023)

Background: Anemia caused by C3-mediated extravascular hemolysis (EVH) commonly occurs in patients (pts) with PNH receiving standard-of-care (SoC) anti-C5 therapies. Iptacopan (IPTA) is a first-in-class, oral, selective complement factor B inhibitor. In the 24-week randomized period of the open-label, multicenter, Phase III APPLY-PNH trial (NCT04558918), IPTA monotherapy had superior efficacy to SoC (Peffault de Latour et al. Blood 2022). Aims: We report total PNH red blood cell (RBC) clone size and C3 deposition data from the 24-week randomized period of APPLY-PNH. Methods: Adult PNH pts (N=97) with mean hemoglobin (Hb) <10 g/dL on stable SoC treatment (eculizumab/ravulizumab) for ≥6 months were randomized 8:5 (stratified by SoC therapy and RBC transfusions [RBCTs] in the preceding 6 months) to take IPTA monotherapy 200 mg twice daily (n=62) or continue their SoC regimen for 24 weeks (n=35). Response defined as a ≥2 g/dL Hb increase from baseline (BL) and response defined as Hb ≥12 g/dL, each in the absence of RBCTs, were primary endpoints. A prespecified testing procedure adjusted for multiplicity; unadjusted, two-sided P values are reported for significant endpoints. Total PNH RBC clone size and C3 deposition were exploratory endpoints assessed by flow cytometry. Results: IPTA monotherapy was superior to SoC for both primary endpoints: an estimated 82.3% of IPTA-treated vs. 2.0% of SoC-treated pts had a ≥2 g/dL Hb increase from BL (difference: 80.3% [95% confidence interval (CI) 71.3, 87.6]; P<0.0001); an estimated 68.8% vs. 1.8% achieved Hb ≥12 g/dL, respectively (difference: 67.0% [95% CI 56.3, 76.9]; P<0.0001). IPTA monotherapy was superior to SoC for RBCT avoidance (difference: 70.3% [95% CI 52.6, 84.9]; P<0.0001), adjusted mean changes from BL in Hb (difference: +3.63 g/dL [95% CI 3.18, 4.08]; P<0.0001), Functional Assessment of Chronic Illness Therapy − Fatigue score (difference: +8.29 [95% CI 5.28, 11.29]; P<0.0001) and absolute reticulocyte count (difference: −116.26 x 109/L [95% CI −132.17, −100.36]; P<0.0001]), and annualized clinical breakthrough hemolysis (BTH) rate (rate ratio: 0.10 [95% CI 0.02, 0.61]; P=0.0118). Lactate dehydrogenase level and annualized major adverse vascular event rate did not differ significantly between arms. In the IPTA arm, mean total PNH RBC clone size (64.6% at BL) increased by week 4, reaching a maximum of 93.4% at week 16 and stabilizing through week 24 (93.2%; change from BL: +28.6%; Figure); mirroring this effect, mean C3 deposition (19.2% at BL) reduced by week 4 and became negligible by weeks 16 (0.2%) through 24 (0.3%; change from BL: −19.2%). Mean total PNH clone size and C3 deposition through week 24 were largely comparable to BL in the SoC arm. Headache (16.1% vs. 2.9%) and diarrhea (14.5% vs. 5.7%) were more commonly reported with IPTA vs. SoC. Two SoC-treated vs. no IPTA-treated pts had serious adverse events (AEs) of hemolysis. No AEs led to IPTA/SoC discontinuation or death.Summary/Conclusion: Oral IPTA monotherapy significantly improved Hb levels vs. SoC without the need for RBCTs. By maintaining intravascular hemolysis control and reducing C3 deposition leading to EVH, IPTA monotherapy led to an expected increase in PNH RBC survival to the extent that they formed >90% of the total RBC population. Clinical BTH rate and severity appeared lower with IPTA vs. SoC. IPTA monotherapy was well tolerated with a favorable safety profile. IPTA monotherapy may become a practice-changing, oral, outpatient treatment for PNH pts with a suboptimal response to intravenous eculizumab/ravulizumab and a preferred option for pts with hemolytic PNH. Keywords: Hemolysis, Complement, Paroxysmal nocturnal hemoglobinuria (PNH), Phase III